Continuing Education Activity
Amebic encephalitis is a rare but lethal central nervous system infection caused by free-living amoebae found in freshwater, lakes, and rivers. There are 2 types of amebic encephalitis, namely primary meningoencephalitis (PAM) and granulomatous amebic encephalitis (GAE). This activity discusses the role of the healthcare team and describes the causative agent of amebic meningoencephalitis, its pathophysiology, clinical presentation, and highlights measures of prevention.
- Review the causative agents of amebic encephalitis.
- Describe the clinical presentation of amebic encephalitis and the plan the diagnostic evaluation and treatment.
- Summarize the treatment and management options available for amebic encephalitis.
- Outline the measures to prevent the disease and the treatment by the interprofessional team that will decrease the number of cases and improve outcomes.
Free-living amebas are protozoan parasites that exist in the environment, mainly freshwater, lakes, and rivers without the need for a definitive host. In humans, there are three main genera of amebas than can cause disease, namely Naegleria fowleri, Acanthamoeba species, and Balamuthia mandrillaris. The amebas have a propensity to cause central nervous system infections, but Acanthamoeba is well-known to cause keratitis and disseminated infections as well. 
These free-living amebas can cause two distinct clinical syndromes, primary amebic meningoencephalitis (PAM) and granulomatous amebic encephalitis (GAE). The initial symptoms of PAM are indistinguishable from bacterial meningitis, while the symptoms of GAM can mimic a brain abscess, encephalitis, or meningitis. These infections are almost uniformly fatal. The mortality rate is above 90%, despite antimicrobial therapy. 
PAM is caused by Naegleria fowleri, which is a thermophilic, free-living ameba that lives in temperatures above 30 C and can tolerate temperatures up to 45 C. This protozoan parasite is found in the soil as well as freshwater, such as ponds, lakes, rivers, streams, hot springs, unchlorinated swimming pools. Risk factors for infection include swimming, diving, waterskiing, surfing, and exposure to hot springs. The use of tap water for nasal irrigation has also been reported as a risk factor for the disease. 
GAE is a subacute to chronic infection of the CNS caused by Acanthamoeba species such as A.culbertsoni, A. polyphagia, A.castellani, A.astronyxis, A.hatchetti, A.rhysodes, A. divionensis, A.lugdunensis, A. lenticulata, and A. haely, and B. mandrillaris. Acanthamoeba is found in soil as well as brackish water, sewage, and humidifiers.
PAM and GAE are very rare disease processes, with only 3.7 cases reported per year worldwide. PAM is more common in warmer regions such as the southern part of the United States and generally occur in the warmer months of spring and summer, possibly due to the increased likelihood of participation in waterborne activities. The mean age of patients affected by PAM was 12 years (range 8 months-66 years); 79% were males. 
PAM occurs in healthy young individuals exposed to warm, freshwater. Naegleria fowleri infects susceptible individuals when contaminated water enters the body through the nose. Trophozoites penetrate the olfactory mucosa, cross the cribriform plates, and ultimately reach the olfactory bulb and cause the inflammatory reaction and the parenchymal damage associated with PAM. 
GAE occurs when the infective form of Acanthamoeba, the trophozoites, enters the body through the eyes, nasal passages, and respiratory tract or ulcerated skin. Once it gains entry, the parasite invades the central nervous system by hematogenous dissemination resulting in GAE. Once in the central nervous system, the parasite stimulates abscess and focal granuloma formation. Disseminated disease, skin disease, and keratitis can also occur.
Naegleria fowleri has a 3 stage life cycle: amoeboid trophozoites, flagellate, and cysts. Hostile environmental changes can cause the trophozoites to change to the flagellated form, and the parasite will revert when conditions improved. Naegleria fowleri trophozoites are found in cerebrospinal fluid (CSF) and tissue, and occasionally, flagellated forms may be noted in the CSF. Cysts are not seen in brain tissue. 
To the contrary, Acanthamoeba exists in only two forms, cysts, and trophozoites. The trophozoites are the infective forms. Both Acanthamoeba spp. cysts and trophozoites are found in tissue. 
History and Physical
Patients with PAM typically present acutely with fever, severe headache, photophobia, nausea, vomiting, behavioral abnormalities, seizures, and altered mental status. A history of olfactory and taste abnormalities are frequently associated with PAM. Patients with PAM typically have a history of swimming, diving, bathing, or playing in warm, generally stagnant, freshwater during the previous 1-9 days. On physical examination, meningismus and cranial nerve palsies can be seen. The disease progresses rapidly with increased intracranial pressure leading to uncal herniation and death. 
The clinical presentation of GAE differs from PAM considerably. GAE presents as a subacute to chronic disease processes with weeks to months of progressive headache, low-grade fevers, visual disturbances, behavioral abnormalities, and focal neurologic deficits. Ultimately, the patient develops increased intracranial pressure, seizures, coma, and death. 
Lumbar puncture for cerebral spinal fluid (CSF) analysis is the primary diagnostic tool for PAM, whereas tissue diagnosis is essential for GAE. Unfortunately, amebic meningoencephalitis is very rarely diagnosed before autopsy. Laboratory findings suggestive of PAM include leukocytosis with a left shift. The CSF opening pressure is very high. The cerebrospinal fluid (CSF) white cell count ranges from 300 to 26,000 cells/mm with polymorphonuclear predominance. CSF red blood cells are usually seen, and hemorrhagic fluid is seen as the disease progresses. Hypoglycorrhachia and elevated protein are characteristic.
Definitive diagnosis is made by observation of motile trophozoites on centrifuged CSF wet mount preparation. Giemsa or trichrome stains help in identifying morphologic features of the trophozoites. The diagnosis can also be made by the use of laboratory testing for Naegleria fowleri nucleic acid in CSF, biopsy, or tissue specimens, or Naegleria fowleri antigen in CSF, biopsy, or tissue specimens.
In order to establish the diagnosis of GAE, brain tissue demonstrating trophozoites and cysts is needed. Moderate granulomatous inflammation with prominent vascular involvement is typically present on brain biopsy. CSF parameters show mild pleocytosis with lymphocytic predominance, high protein concentration, and low or normal glucose concentration. Rarely, Acanthamoeba trophozoites may be seen on Giemsa stain of the CSF sediment. Head computed tomography (CT) scanning or magnetic resonance imaging (MRI) should precede lumbar puncture if clinical signs of focal CNS involvement or elevated intracranial pressure (ICP) is present.
Magnetic resonance imaging of the brain shows the presence of single or multiple space-occupying lesions with ring enhancement. Computed tomography may show progressive hydrocephalus, meningeal thickening, pseudotumoral lesions, largely isolated lesions, or multifocal ring-enhancing lesions. On post-mortem examination, significant edema and hemorrhage of the brain are seen. 
Treatment / Management
Due to the rarity of the disease and lack of clinical trials, the definitive treatment for GAE is not clear at this time. A combination of drugs is used. The Centers for Disease Control and Prevention recommend combination treatment with pentamidine, sulfadiazine, flucytosine, and either fluconazole or itraconazole. Multiple other regimens are also recommended. Chronic Acanthamoeba meningitis was successfully treated in 2 children with a combination of oral trimethoprim/ sulfamethoxazole, rifampin, and ketoconazole. Resection of brain lesions may help as well. 
Similarly, the optimal treatment of PAM is not known. For the treatment of PAM amphotericin B, both intravenously and intrathecally is recommended, but considering the fulminant course of the disease and high mortality rates, a combination of drugs is generally used. Reports include the use of amphotericin in addition to rifampin, fluconazole, miltefosine, and azithromycin. Posaconazole has also been shown to be effective in mouse models of disease. 
The clinical presentation of PAM is very similar to acute bacterial meningitis, and CSF parameters are also alike. Therefore, obtaining an epidemiological history in patients with suspected bacterial meningitis but negative cultures and failure to improve cannot be emphasized enough.
The differential diagnosis of GAE includes bacterial brain abscesses, tuberculosis, Nocardia, CNS aspergillosis, cryptococcosis, and Histoplasma. Toxoplasmosis and cysticercosis, as well as CNS lymphoma, should be considered.
PAM is associated with an extremely high mortality rate. Studies have reported a case-fatality rate of as high as 99%. The mean time from onset of symptoms to death was 5.3 days (range 1-12 days), and the mean time from exposure to death was 9.9 days (range 6-17 days).
Deterrence and Patient Education
Measures to prevent primary amebic meningoencephalitis due to Naegleria include the following:
- Avoidance of diving and jumping into stagnant, freshwater.
- Consider the use of nose plugs for unavoidable exposures or pinching your nose shut when diving or swimming in freshwater.
- Keep your head above water when swimming in freshwater, hot springs, and other untreated thermal bodies of water.
- When participating in water-related activities, avoid digging, or stirring up, the sediment.
- Use boiled, filtered, or sterile water, not tap water for nasal or sinus irrigation.
Measure to prevent GAE and keratitis due to Acanthamoeba include:
- Replace contacts as prescribed.
- Remove lenses before activity involving contact with water.
- Wash hands with soap before handling contact lenses and clean lenses as instructed by the manufacturer.
Enhancing Healthcare Team Outcomes
Amebic encephalitis is both an exceptionally rare and highly lethal central nervous system infection caused by free-living amoebae, found in freshwater, lakes, and rivers. There are two types of amebic encephalitis: primary amebic meningoencephalitis and granulomatous amebic encephalitis. The initial symptoms of PAM are indistinguishable from bacterial meningitis, while the symptoms of GAM can mimic a brain abscess or meningitis.
These infections are almost always fatal. The high mortality rate is due to a lack of optimal treatment, the rarity of the disease, and delays in diagnosis.
Clinicians working in communities where there is a potential for exposure to large stagnant bodies of freshwater should play a role in educating patients about the risk and provide information about how to mitigate the risk. If the disease is being considered in the differential diagnosis of a patient, early laboratory evaluation, and emergent consultations with infectious disease specialists, neurologists, and neurosurgeons are recommended to facilitate prompt diagnosis and treatment.
Patients with amebic meningoencephalitis may require monitoring in the intensive care unit. A hypothermia protocol may be considered as this has been shown to increase survival. An interprofessional team, including intensivists, nurses, social work, and pharmacists, may help in facilitating support to the family and provide updates regarding the condition and prognosis of the patient. Intensive care nurses monitor patients and notify the team of changes in status. The few reported survivors have been left with severe neurological disability and sequelae of encephalitis. Infectious disease pharmacists review treatment and check for drug-drug interactions. [Level 5]